U.S. patent application number 17/680362 was filed with the patent office on 2022-09-08 for key intermediate for synthesis of prostaglandin compound and preparation method thereof.
The applicant listed for this patent is SHENZHEN CATALYS TECHNOLOGY CO., LTD. Invention is credited to XIAOBING DING, SHUANG GAO, QIWEI LANG, WEI SU.
Application Number | 20220281797 17/680362 |
Document ID | / |
Family ID | 1000006380904 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220281797 |
Kind Code |
A1 |
DING; XIAOBING ; et
al. |
September 8, 2022 |
KEY INTERMEDIATE FOR SYNTHESIS OF PROSTAGLANDIN COMPOUND AND
PREPARATION METHOD THEREOF
Abstract
The present invention relates to the technical field of organic
chemical engineering, and in particular to a key intermediate for
synthesizing prostaglandin compounds and a preparation method
therefor. When applied to the synthesis of prostaglandin compounds,
the process flow is simplified, the yield and product purity are
improved, the production costs are reduced, and the industrial
application is easy. ##STR00001##
Inventors: |
DING; XIAOBING; (HANGZHOU,
CN) ; LANG; QIWEI; (HANGZHOU, CN) ; SU;
WEI; (HANGZHOU, CN) ; GAO; SHUANG; (HANGZHOU,
CN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SHENZHEN CATALYS TECHNOLOGY CO., LTD |
Shenzhen |
|
CN |
|
|
Family ID: |
1000006380904 |
Appl. No.: |
17/680362 |
Filed: |
February 25, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
PCT/CN2021/117634 |
Sep 10, 2021 |
|
|
|
17680362 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 59/48 20130101;
C07C 59/46 20130101; C07C 33/20 20130101; C07C 43/23 20130101; C07F
7/1804 20130101; C07C 49/757 20130101; C07D 317/12 20130101; C07C
33/025 20130101; C07C 2601/08 20170501; C07D 307/935 20130101 |
International
Class: |
C07C 59/48 20060101
C07C059/48; C07D 317/12 20060101 C07D317/12; C07F 7/18 20060101
C07F007/18; C07D 307/935 20060101 C07D307/935; C07C 49/757 20060101
C07C049/757; C07C 33/025 20060101 C07C033/025; C07C 33/20 20060101
C07C033/20; C07C 43/23 20060101 C07C043/23; C07C 59/46 20060101
C07C059/46 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 16, 2020 |
CN |
202010978194.8 |
Claims
1. A key intermediate for synthesis of a prostaglandin compound,
having a structure shown below: ##STR00071## wherein denotes a
single bond or double bond, and if it is a double bond, R.sup.1 is
absent; and wherein R.sup.1 and R.sup.2 are each H or protecting
groups; R.sup.3 and R.sup.4 are the same or different alkyl or
aryl, or R.sup.3 and R.sup.4 form a ring; and R.sup.5 and R.sup.6
are the same or different H, alkyl, or aryl.
2. The key intermediate for the synthesis of the prostaglandin
compound according to claim 1, having a structure shown below:
##STR00072## wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as
defined above.
3. The key intermediate for the synthesis of the prostaglandin
compound according to claim 1, which is ##STR00073## wherein
R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined above.
4. The key intermediate for the synthesis of the prostaglandin
compound according to claim 1, which is ##STR00074## wherein
R.sup.1 and R.sup.2 are as defined above, and n is an integer from
1 to 3.
5. The key intermediate for the synthesis of the prostaglandin
compound according to claim 1, wherein the intermediate is selected
from: ##STR00075## wherein P is a protecting group.
6. The key intermediate for the synthesis of the prostaglandin
compound according to claim 1, wherein the protecting group is
selected from an ether protecting group, an acyl protecting group,
a silyl ether protecting group, an acetal protecting group.
7. The key intermediate for the synthesis of the prostaglandin
compound according to claim 1, wherein the intermediate is selected
from: ##STR00076##
8. A method for preparing the key intermediate for the synthesis of
the prostaglandin compound according to claim 1, comprising steps
of: a) asymmetrically reducing compound S1 to obtain chiral alcohol
compound S2, and then protecting hydroxyl group of the chiral
alcohol compound S2 with silane to obtain Weinreb amide compound
S3; b) subjecting the Weinreb amide compound S3 to an addition
reaction with an alkyne reagent to obtain enyne compound S4; c)
subjecting the enyne compound S4 to a Zhang enyne
cycloisomerization to obtain five-membered ring S5; d) conjugating
the five-membered ring S5 to reduce double bond thereof to obtain
compound S6, and further reducing ketone of the compound S6 to
obtain compound S7; and e) deprotecting the compound S7 by removing
TIPS thereof to obtain compound S8; referring to the following
reaction route: ##STR00077##
9. A method for preparing a prostaglandin compound, comprising
preparing the prostaglandin compound by the key intermediate for
the synthesis of the prostaglandin compound according to claim
1.
10. The method for preparing the prostaglandin compound according
to claim 9, wherein the prostaglandin compound is selected from:
##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082##
##STR00083##
Description
TECHNICAL FIELD
[0001] The present invention relates to the technical field of
organic chemical engineering, and particularly to a key
intermediate for the synthesis of a prostaglandin compound and a
preparation method thereof.
BACKGROUND
[0002] Prostaglandins are a class of important endogenous products
with a variety of physiological activities, and many derivatives
obtained therefrom by modifying their structures also have
important physiological activities. At present, a number of
compounds are available in the market for the treatment of
glaucoma, ulcer, early pregnancy, constipation and high blood
pressure and the like. The prostaglandin compounds include, but are
not limited to,
##STR00002## ##STR00003## ##STR00004## ##STR00005## ##STR00006##
##STR00007##
[0003] The synthetic routes for preparing the aforementioned
compounds in the prior art mainly include:
##STR00008##
##STR00009##
[0004] Although many molecules of the prostaglandin family can be
obtained from Corey lactone, a key intermediate in the Corey's
route through subsequent conversion, the synthesis procedure of
this intermediate is complicated, which include nine steps of
reactions starting from cyclopentadiene, and the subsequent
conversion from the intermediate to the final product also requires
nearly ten steps or even more than ten steps of reactions.
##STR00010##
[0005] The synthesis procedure of Aggarwal's route is simple.
However, the yield of the first-step reaction is very low, and only
14%, causing it difficult to be scaled up for use. The conversion
of the key intermediate to the final product is also difficult, and
the chemical selectivity of the reaction is poor, with a low
yield.
##STR00011##
[0006] The Shi's route refers to a racemic reaction, and a further
resolution is required to obtain the prostaglandin compound.
##STR00012##
[0007] The Stork's route involves a key intermediate
cyclopentenone. The synthesis of this intermediate is difficult,
and generally realized by an enzymatic resolution reaction, which
is adverse to atomic economy. Moreover, the conversion steps from
this intermediate to the final product are troublesome, in which an
organocopper lithium reagent that is sensitive to water and air is
used, causing difficulty in operation.
##STR00013##
[0008] The Noyori's route also involves the
difficult-to-be-synthesized cyclopentenone intermediate, and the
organocopper lithium reagent that is sensitive to water and air, as
well as a highly toxic organotin reagent, causing great harm to the
humans and environment.
[0009] When used for the synthesis of prostaglandin compounds, the
aforementioned procedures are complex, and the yield and product
purity need to be further improved.
[0010] The present invention aims to provide a key intermediate for
the synthesis of a prostaglandin compound and a preparation method
thereof, for use in the synthesis of a prostaglandin. The present
invention has the advantages of simple reaction operation, good
functional group tolerance, no highly toxic chemicals involved in
the synthetic route, being green and environmentally friendly, high
yield and purity of the product, and more conducive to industrial
application.
SUMMARY
[0011] In view of the problems existing in the prior art, the
present invention provides a key intermediate for the synthesis of
a prostaglandin compound and a preparation method thereof.
Particularly, the present invention is accomplished through the
following technical solutions.
[0012] A key intermediate for the synthesis of a prostaglandin
compound has a structure shown below:
##STR00014##
wherein denotes a single bond or double bond, and if it is a double
bond, R.sup.1 is absent; and wherein R.sup.1 and R.sup.2 are each H
or protecting groups; R.sup.3 and R.sup.4 are the same or different
alkyl or aryl, or R.sup.3 and R.sup.4 form a ring; and R.sup.5 and
R.sup.6 are the same or different H, alkyl, or aryl.
[0013] The alkyl refers to a linear or branched alkyl group,
including, but not limited to, For example, a C.sub.1-6 alkyl group
or a C.sub.3-7 monocyclic cycloalkyl group.
[0014] The C.sub.1-6 alkyl group is selected from methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,
isopentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, isohexyl,
neohexyl, s-hexyl, and t-hexyl.
[0015] The C.sub.3-7 monocyclic cycloalkyl group is selected from
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and
cycloheptyl.
[0016] The aryl refers to an aromatic ring structure containing a
single ring or a fused polycyclic ring, including, but not limited
to, naphthyl and the like. Further, the aryl group can be
substituted with one or more halogens or alkyl groups.
[0017] R.sup.3 and R.sup.4 form a ring by connecting the carbon
chains, wherein one or more carbon atoms in the carbon chains can
be replaced by a heteroatom selected from O, N and S.
[0018] In a preferred embodiment of the present invention, the key
intermediate for the synthesis of a prostaglandin compound has a
structure shown below:
##STR00015##
[0019] wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as
defined above.
[0020] In a preferred embodiment of the present invention, the key
intermediate for the synthesis of a prostaglandin compound has a
structure shown below:
##STR00016##
[0021] wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as
defined above.
[0022] In a preferred embodiment of the present invention, the key
intermediate for the synthesis of a prostaglandin compound has a
structure shown below:
##STR00017##
[0023] wherein R.sup.1 and R.sup.2 are as defined above, and n is
an integer from 1 to 3.
[0024] In a preferred embodiment of the present invention, the key
intermediate for the synthesis of a prostaglandin compound has a
structure shown below:
##STR00018##
[0025] wherein P is a protecting group.
[0026] In a preferred embodiment of the present invention, the
protecting group is selected from an ether protecting group, an
acyl protecting group, a silyl ether protecting group, an acetal
protecting group, or other common protecting groups in chemical
synthesis.
[0027] The ether protecting group includes, for example, methyl or
substituted methyl, preferably lower alkoxymethyl, particularly
methoxymethyl (MOM), methylthiomethyl, p-nitrobenzyloxymethyl,
guaiacylolmethyl, lower alkoxy-lower alkoxymethyl, particularly
Preferably 2-methoxyethoxymethyl (MEM), and
2,2,2-trifluoroethoxymethyl; tetrahydropyrans;
3-bromotetrahydropyrans; substituted ethyl, such as 1-ethoxyethyl,
1-(2-chloroethoxy)ethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl;
substituted phenyl ethers, such as p-chlorophenyl, P-methoxyphenyl,
and p-nitrophenyl; and silyl ethers, such as trimethylsilyl,
triethylsilyl, triisopropylsilyl, and dimethylisopropylsilyl,
etc.
[0028] In a preferred embodiment of the present invention, the key
intermediate for the synthesis of a prostaglandin compound has a
structure shown below:
##STR00019##
[0029] In a preferred embodiment of the present invention, a method
for preparing the key intermediate comprises steps of:
[0030] a) asymmetrically reducing compound S1 to obtain chiral
alcohol compound S2, and then protecting hydroxyl group of the
chiral alcohol compound S2 with silane to obtain Weinreb amide
compound S3;
[0031] b) subjecting the Weinreb amide compound S3 to an addition
reaction with an alkyne reagent to obtain enyne compound S4;
[0032] c) subjecting the enyne compound S4 to a Zhang enyne
cycloisomerization to obtain five-membered ring S5;
[0033] d) conjugating the five-membered ring S5 to reduce double
bond thereof to obtain compound S6, and further reducing ketone of
the compound S6 to obtain compound S7; and
[0034] e) deprotecting the compound S7 by removing TIPS thereof to
obtain compound S8; referring to the following reaction route:
##STR00020## ##STR00021##
[0035] Other intermediates described above can be synthesized based
on this synthetic route by adaptively adjusting the groups.
[0036] In a preferred embodiment of the present invention, the
preparation method is as follows:
##STR00022##
[0037] In a preferred embodiment of the present invention, the
aforementioned key intermediate for the synthesis of a
prostaglandin compound is used to prepare the prostaglandin
compound.
[0038] In a preferred embodiment of the present invention, the
aforementioned key intermediate for the synthesis of a
prostaglandin compound is reacted with intermediates represented by
the following formulas to prepare the prostaglandin compounds. The
intermediate is selected from:
##STR00023##
[0039] In a preferred embodiment of the present invention, the
intermediate is prepared by the following preparation method,
wherein R is the corresponding group in the aforementioned
intermediate compound:
##STR00024##
[0040] In a preferred embodiment of the present invention, the
intermediate is prepared by the following preparation method:
##STR00025##
[0041] In a preferred embodiment of the present invention, the
intermediate is prepared by the following preparation method:
##STR00026##
[0042] In a preferred embodiment of the present invention, the
prostaglandin compound is selected from:
##STR00027## ##STR00028## ##STR00029## ##STR00030## ##STR00031##
##STR00032##
[0043] Beneficial effects of the present invention over the prior
art:
[0044] The key intermediate is used in the synthesis of the
prostaglandin compound, the present invention has advantages of
simplified process, highly environmentally tolerant functional
groups of the intermediate, no highly toxic chemicals involved in
the synthetic route, being green and environmentally friendly,
improved yield and product purity, reduced production cost, and
easy industrialization.
[0045] With respect to the synthetic route, the synthetic route
provided by the present invention starts from different
intermediates to prepare different prostaglandin compounds of
different skeletal structures. Therefore, compared with other
routes, it can be widely used in the synthesis of various
prostaglandin compounds.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] FIG. 1 shows the structures of a specific intermediate
according to the present application and prostaglandin
compounds.
DESCRIPTION OF THE EMBODIMENTS
[0047] The present invention will be further described in detail
below with reference to examples and accompanying drawings.
However, the present invention is not limited thereto.
Example 1
##STR00033## ##STR00034##
[0049] Step 1:
##STR00035##
[0050] Hydrogenation step of 1 mmol substrate (S/C=1000): In an
argon-filled glove box, f-amphox (5.52 mg, 0.01 mmol) and a metal
precursor [Ir(COD)Cl].sub.2 (3.35 mg, 0.05 mmol) were dissolved in
anhydrous and anaerobic i-PrOH (1 mL), stirred at room temperature
for 1 hr, to obtain a catalyst solution of 10 .mu.mol/mL. In the
glove box, Compound S1 (171 mg, 1 mmol) was dissolved in a 20 mL
reaction flask containing 10 mL of anhydrous and anaerobic toluene,
then MeOK (0.7 mg, 0.01 mmol) was added to the reaction system, and
finally 0.1 mL of the fresh catalyst prepared above was added. The
reaction flask was transferred to a hydrogenation reactor, and the
reactor was purged three times with hydrogen and then introduced
with 40 atm of hydrogen. The reaction system was stirred for 24 hrs
at room temperature. After the reaction, hydrogen in the reactor
was discharged, and the reaction solution was dried by rotary
evaporation. The obtained crude product was subjected to silica gel
column chromatography with eluent of petroleum ether:ethyl
acetate=2:1, to obtain 150 mg of a liquid product S2 as a light
yellow oil (yield 88%).
[0051] Step 2:
##STR00036##
[0052] Compound S2 (1.73 g, 10 mmol) and 10 mL of dry DCM were
added to a 25 mL reaction flask, and then 2, 6-lutidine (1.6 g, 15
mmol) was added to the reaction system. Finally, TIPSOTf (3.67 g,
12 mmol) was slowly added dropwise to the reaction solution, and
reacted at room temperature for 30 minutes. The reaction was
monitored by TLC. After the reaction was completed, water was added
to stop the reaction. The reaction solution was extracted with DCM
(20 mL*3), and the organic phases were combined with anhydrous
sodium sulfate and dried with anhydrous sodium sulfate by rotary
evaporation. The obtained crude product was subjected to silica gel
column chromatography with eluent of petroleum ether:ethyl
acetate=4:1, to obtain 3.28 g of a liquid product S3 as a light
yellow oil (yield 99%).
[0053] Step 3:
##STR00037##
[0054] Under an argon atmosphere at -78.degree. C., Compound S3
(294 mg, 3 mmol) and 5 mL of anhydrous THF were added to a 25 mL
dry reaction flask, and then 1.25 mL (2.4 M, 3 mmol) of n-butyl
lithium was added dropwise to the reaction solution, and reacted at
-78.degree. C. for 30 minutes. Then Compound (328 mg, 1 mmol) was
dissolved in 2 mL of dry THF, and slowly added dropwise to the
above reaction solution. The reaction solution was then immediately
heated to -10.degree. C., and continuously reacted for 30 minutes.
The reaction was monitored by TLC. After the reaction was
completed, the reaction was terminated by adding a saturated
ammonium chloride aqueous solution. The reaction solution was
extracted with ethyl acetate (5 mL*3), and the organic phases were
combined, and dried with anhydrous sodium sulfate by rotary
evaporation. The obtained crude product was subjected to silica gel
column chromatography with eluent of petroleum ether:ethyl
acetate=20:1, to obtain 351 mg of a liquid product S4 as a light
yellow oil (yield 96%).
[0055] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 5.78 (s, 1H),
5.65-5.56 (m, 1H), 5.43 (dd, J=15.2, 7.3 Hz, 1H), 4.72 (dd, J=13.3,
6.5 Hz, 1H), 4.10-3.99 (m, 2H), 3.99-3.88 (m, 2H), 2.84 (dd,
J=14.8, 6.6 Hz, 1H), 2.68 (dd, J=14.8, 6.3 Hz, 1H), 1.64 (d, J=6.3
Hz, 3H), 1.01 (s, 21H). .sup.13C NMR (151 MHz, CDCl.sub.3) .delta.
184.67 (s), 133.21 (s), 126.61 (s), 92.51 (s), 85.37 (s), 82.66
(s), 70.22 (s), 64.56 (s), 54.40 (s), 17.96 (s), 17.90 (s), 17.60
(s), 17.34 (s), 12.26 (s).
[0056] Step 4:
##STR00038##
[0057] In an argon-filled glove box, Compound S4 (3.28 g, 9 mmol)
was dissolved in a 100 mL reaction flask containing 50 mL of
anhydrous and anaerobic DCE. (S)-BINAP (0.558 g, 0.9 mmol) and
[Rh(COD)Cl].sub.2 (0.22 g, 0.45 mmol) were added to the reaction
flask and stirred at room temperature for 5 minutes. Finally,
AgSbF.sub.6 (0.614 g, 1.8 mmol) was added and continuously reacted
at room temperature for 10 minutes. The reaction was monitored by
TLC. After the reaction was completed, the reaction solution was
dried by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=12:1, to obtain 2.78 g of a liquid
product S5 as a light yellow oil (yield 85%).
[0058] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.33 (d, J=7.4 Hz,
1H), 5.73-5.69 (m, 1H), 5.69-5.64 (m, 1H), 5.24 (dd, J=29.5, 13.6
Hz, 2H), 4.24 (q, J=6.7 Hz, 1H), 4.05-3.97 (m, 2H), 3.96-3.90 (m,
2H), 3.31 (t, J=6.0 Hz, 1H), 2.72 (dd, J=17.9, 6.4 Hz, 1H), 2.40
(dd, J=17.9, 7.2 Hz, 1H), 1.03 (s, 21H). .sup.13C NMR (151 MHz,
CDCl.sub.3) .delta. 203.43 (s), 142.37 (s), 136.27 (s), 135.06 (s),
119.54 (s), 96.84 (s), 72.37 (s), 65.20 (d, J=5.6 Hz), 57.37 (s),
48.52 (s), 17.93 (s), 17.90 (s), 12.13 (s).
[0059] Step 5:
##STR00039##
[0060] Under an argon atmosphere, Compound S5 (366 mg, 1 mmol),
anhydrous ZnCl.sub.2 (204 mg, 1.5 mmol), (Ph.sub.3P).sub.4Pd (23.1
mg, 0.02 mmol) and 5 mL anhydrous THF were sequentially added to a
10 mL dry reaction flask. Then Ph.sub.2SiH.sub.2 (312 mg, 1.7 mmol)
was added dropwise into the reaction flask, and reacted at
50.degree. C. for 1 hr. The reaction was monitored by TLC. After
the reaction was completed, the reaction was terminated by adding a
saturated ammonium chloride aqueous solution. The reaction solution
was extracted with ethyl acetate (5 mL*3), and the organic phases
were combined, and dried with anhydrous sodium sulfate by rotary
evaporation. The obtained crude product was subjected to silica gel
column chromatography with eluent of petroleum ether:ethyl
acetate=20:1, to obtain 329 mg of a liquid product S6 as a light
yellow oil (yield 90%).
[0061] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 5.84-5.73 (m, 1H),
5.19 (dd, J=21.0, 13.7 Hz, 2H), 5.13 (t, J=5.2 Hz, 1H), 4.22 (q,
J=7.2 Hz, 1H), 3.98-3.89 (m, 2H), 3.88-3.79 (m, 2H), 2.69 (dd,
J=18.1, 6.8 Hz, 1H), 2.61 (dd, J=18.1, 7.9 Hz, 1H), 2.25 (ddd,
J=16.7, 14.7, 6.9 Hz, 2H), 2.06-1.98 (m, 1H), 1.82 (dt, J=12.1, 5.8
Hz, 1H), 1.04 (s, 21H). .sup.13C NMR (151 MHz, CDCl.sub.3) .delta.
215.26 (s), 138.07 (s), 117.66 (s), 102.42 (s), 73.18 (s), 64.80
(s), 64.63 (s), 55.82 (s), 49.36 (s), 47.37 (s), 32.55 (s), 17.95
(d, J=5.5 Hz), 12.16 (s).
[0062] Step 6:
##STR00040##
[0063] Under an argon atmosphere at -78.degree. C., Compound S6
(368 mg, 1 mmol) and 5 mL of anhydrous THF were added to a 25 mL
dry reaction flask, and then 1.2 mL (1 M, 1.2 mmol) of L-Selectride
was added dropwise into the reaction solution, and reacted at
-78.degree. C. for 30 minutes. The reaction was monitored by TLC.
After the reaction was completed, the reaction was terminated by
adding a saturated ammonium chloride aqueous solution. The reaction
solution was extracted with ethyl acetate (5 mL*3), and the organic
phases were combined, and dried with anhydrous sodium sulfate by
rotary evaporation. The obtained crude product was subjected to
silica gel column chromatography with eluent of petroleum
ether:ethyl acetate=8:1, to obtain 312 mg of a liquid product S7 as
a light yellow oil (yield 85%).
[0064] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.60 (dt, J=17.1,
9.6 Hz, 1H), 5.19-4.96 (m, 2H), 4.93 (t, J=4.5 Hz, 1H), 4.17 (td,
J=7.2, 2.1 Hz, 1H), 4.06 (dd, J=11.2, 4.9 Hz, 1H), 4.03-3.92 (m,
2H), 3.90-3.79 (m, 2H), 3.04 (d, J=6.4 Hz, 1H), 2.33 (td, J=9.6,
5.2 Hz, 1H), 2.16 (dt, J=13.9, 6.1 Hz, 1H), 2.08-1.92 (m, 1H), 1.82
(dt, J=14.2, 4.0 Hz, 2H), 1.75-1.68 (m, 1H), 1.04 (s, 21H).
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 139.57 (s), 116.20 (s),
103.90 (s), 78.41 (s), 72.73 (s), 64.97 (s), 64.63 (s), 57.64 (s),
44.94 (s), 43.13 (s), 31.64 (s), 17.97 (s), 12.05 (s).
[0065] Step 7:
##STR00041##
[0066] Compound S7 (370 mg, 1 mmol) and 5 mL of anhydrous THF were
added to a 25 mL dry reaction flask, and then 1.5 mL (1 M in THF,
1.5 mmol) of TBAF was added dropwise to the reaction solution, and
reacted at room temperature for 30 minutes. The reaction was
monitored by TLC. After the reaction was completed, the reaction
solution was extracted with Et.sub.2O (5 mL*3), and the organic
phases were combined, and dried with anhydrous sodium sulfate by
rotary evaporation. The obtained crude product was subjected to
silica gel column chromatography with eluent of petroleum
ether:ethyl acetate=2:1, to obtain 337 mg of a liquid product S8 as
a light yellow oil (yield 91%).
[0067] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.62 (ddd, J=17.1,
10.1, 8.9 Hz, 1H), 5.16-5.01 (m, 2H), 4.89 (dd, J=5.1, 3.0 Hz, 1H),
4.22 (d, J=4.9 Hz, 1H), 4.05-3.93 (m, 2H), 3.92-3.81 (m, 3H), 3.10
(s, 1H), 2.54 (s, 1H), 2.34-2.20 (m, 2H), 1.96-1.82 (m, 2H),
1.79-1.67 (m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta.
139.06 (s), 116.58 (s), 103.79 (s), 77.27 (s), 72.33 (s), 65.14
(s), 64.58 (s), 57.59 (s), 44.91 (s), 41.82 (s), 31.15 (s).
Example 2
##STR00042##
[0069] At room temperature, Compound S7 (2 g, 5.4 mmol) and 25 mL
of THF were added to a 100 mL reaction flask, and then 25 mL of 1N
HCl was added dropwise to the reaction solution and reacted at room
temperature for 2 hrs. The reaction was monitored by TLC. After the
reaction was completed, the reaction was terminated by adding a
saturated sodium bicarbonate aqueous solution. The reaction
solution was extracted with ethyl acetate (25 mL*3), and the
organic phases were combined, and dried with anhydrous sodium
sulfate by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=1:1, to obtain 900 mg of a liquid
product S9 as a light yellow oil (yield 98%).
[0070] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.62 (m, 1H),
5.14-5.04 (m, 2H), 4.89 (dd, J=5.1, 3.0 Hz, 1H), 4.22 (t, J=5.1 Hz,
1H), 4.05-3.93 (m, 2H), 3.91-3.80 (m, 3H), 3.10 (br, 1H), 2.54 (br,
1H), 2.33-2.20 (m, 2H), 1.95-1.81 (m, 2H), 1.79-1.68 (m, 2H).
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 139.1, 116.6, 103.8,
77.3, 72.3, 65.1, 64.6, 57.6, 44.9, 41.8, 31.1. HRMS (ESI) Calcd
for C.sub.11H.sub.18O.sub.4Na [M+Na].sup.+: 237.1097, found.
237.1095.
Example 3
##STR00043##
[0072] At room temperature, Compound S6 (1.5 g, 4.1 mmol) and 25 mL
of THF were added to a 100 mL reaction flask, and then 25 mL of 1N
HCl was added dropwise to the reaction solution and reacted at room
temperature for 2 hrs. The reaction was monitored by TLC. After the
reaction was completed, the reaction was terminated by adding a
saturated sodium bicarbonate aqueous solution. The reaction
solution was extracted with ethyl acetate (25 mL*3), and the
organic phases were combined, and dried with anhydrous sodium
sulfate by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=1:1, to obtain 620 mg of a liquid
product S10 as a light yellow oil (yield 90%).
[0073] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 9.73 (s, 1H),
5.76-5.70 (m, 1H), 5.25 (s, 1H), 5.22 (d, J=7.9 Hz, 1H), 4.18 (q,
J=8.2 Hz, 1H), 2.84-2.77 (m, 2H), 2.70 (dd, J=18.7, 5.0 Hz, 1H),
2.56-2.45 (m, 2H), 2.41 (dd, J=18.6, 9.4 Hz, 1H), 2.25 (br, 1H).
.sup.13C NMR (151 MHz, CDCl.sub.3) .delta. 212.5, 199.3, 136.8,
119.4, 72.0, 55.3, 49.0, 45.2, 41.2. HRMS (ESI) Calcd for
C.sub.9H.sub.12O.sub.3Na [M+Na]+: 191.0679, found: 191.0679.
Example 4
[0074] The key intermediate for the synthesis of a prostaglandin
compound was reacted with an intermediate represented by the
following formulas to prepare the prostaglandin compounds.
[0075] The structures of the intermediate is selected from:
##STR00044##
[0076] The preparation route was as follows:
##STR00045##
Example 5
[0077] The preparation method of a specific intermediate in Example
4 was as follows:
##STR00046##
[0078] Step 1:
##STR00047##
[0079] Hydrogenation step (S/C=1000): In an argon-filled glove box,
f-amphox (55.2 mg, 0.1 mmol) and a metal precursor
[Ir(COD)Cl].sub.2 (33.5 mg, 0.5 mmol) were dissolved in anhydrous
and anaerobic i-PrOH (1 mL), stirred at room temperature for 1 hr,
to obtain a catalyst solution of 100 .mu.mol/mL. In the glove box,
Compound SC-1 (2.6 g, 20 mmol) was dissolved in a 100 mL reaction
flask containing 50 mL of anhydrous and anaerobic isopropanol, then
K.sub.2CO.sub.3 (27.8 mg, 0.01 mmol) was added to the reaction
system, and finally 0.2 mL of the fresh catalyst prepared above was
added. The reaction flask was transferred to a hydrogenation
reactor, and the reactor was purged three times with hydrogen and
then introduced with 80 atm of hydrogen. The reaction system was
stirred 24 hrs at room temperature. After the reaction, hydrogen in
the reactor was discharged, and the reaction solution was dried by
rotary evaporation. The obtained crude product was subjected to
silica gel column chromatography with eluent of petroleum
ether:ethyl acetate=2:1, to obtain 2.55 g of a liquid product SC-2
as a light yellow oil (yield 98%).
[0080] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 3.66 (ddd, J=13.9,
9.2, 3.7 Hz, 2H), 3.42 (dd, J=11.0, 7.7 Hz, 1H), 2.49 (s, 2H),
1.47-1.38 (m, 3H), 1.31 (t, J=10.5 Hz, 5H), 0.88 (t, J=6.7 Hz, 3H).
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 72.29 (s), 66.60 (s),
32.93 (s), 31.79 (s), 25.24 (s), 22.49 (s), 13.91 (s).
[0081] Step 2:
##STR00048##
[0082] Under an argon atmosphere at -20.degree. C., (Me).sub.3SI
(26.8 g, 131.5 mmol) and 100 mL of anhydrous THF were added to a
250 mL dry reaction flask, and then 54 mL (2.4 M, 131.5 mmol) of
n-butyl lithium was added dropwise to the reaction solution, and
reacted at -20.degree. C. for 30 minutes. Compound SC-3 (3.0, 26.3
mmol) was dissolved in 10 mL of dry THF, and slowly added dropwise
to the above reaction solution. The reaction solution was then
slowly heated to room temperature, and continuously reacted for 5
hrs. The reaction was monitored by TLC. After the reaction was
completed, the reaction was terminated by adding a saturated
ammonium chloride aqueous solution. The reaction solution was
extracted with ethyl acetate (100 mL*3), and the organic phases
were combined, and dried with anhydrous sodium sulfate by rotary
evaporation. The obtained crude product was subjected to silica gel
column chromatography with eluent of petroleum ether:ethyl
acetate=20:1, to obtain 2.8 g of a liquid product SC-4 as a light
yellow oil (yield 88%).
[0083] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.94-5.79 (m, 1H),
5.15 (ddt, J=43.7, 10.4, 1.4 Hz, 2H), 4.13-4.06 (m, 1H), 1.58-1.48
(m, 3H), 1.35-1.28 (m, 5H), 0.88 (t, J=6.8 Hz, 3H). .sup.13C NMR
(101 MHz, CDCl.sub.3) .delta. 141.30 (s), 114.46 (s), 73.23 (s),
36.95 (s), 31.71 (s), 24.97 (s), 22.56 (s), 13.98 (s).
Example 6
[0084] The preparation method of another specific intermediate in
Example 4 was as follows:
[0085] Step 1:
##STR00049##
[0086] Hydrogenation step (S/C=500): In an argon-filled glove box,
f-amphox (55.2 mg, 0.1 mmol) and a metal precursor
[Ir(COD)Cl].sub.2 (33.5 mg, 0.5 mmol) were dissolved in anhydrous
and anaerobic i-PrOH (1 mL), and stirred at room temperature for 1
hr, to obtain a catalyst solution of 100 .mu.mol/mL. In the glove
box, Compound SC-5-1 (3.28 g, 20 mmol) was dissolved in a 100 mL
reaction flask containing 50 mL of anhydrous and anaerobic
isopropanol, then K.sub.2CO.sub.3 (27.8 mg, 0.01 mmol) was added to
the reaction system, and finally 0.4 mL of the fresh catalyst
prepared above was added. The reaction flask was transferred to a
hydrogenation reactor, and the reactor was purged three times with
hydrogen and then introduced with 50 atm of hydrogen. The reaction
system was stirred 24 hrs at room temperature. After the reaction,
hydrogen in the reactor was discharged, and the reaction solution
was dried by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=2:1, to obtain 3.2 g of a liquid
product SC-6-1 as a light yellow oil (yield 98%).
[0087] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34-7.25 (m, 2H),
7.19 (dd, J=10.6, 4.3 Hz, 3H), 3.72 (tdd, J=7.8, 5.0, 3.1 Hz, 1H),
3.55 (ddd, J=18.8, 11.1, 5.3 Hz, 2H), 2.96-2.62 (m, 4H), 1.84-1.66
(m, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 141.64 (s),
128.42 (s), 128.37 (s), 125.93 (s), 71.52 (s), 66.74 (s), 34.61
(s), 31.76 (s).
[0088] Step 2:
##STR00050##
[0089] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31-7.23 (m, 2H),
7.17 (dd, J=10.7, 4.4 Hz, 3H), 2.92 (dddd, J=6.5, 5.0, 4.0, 2.8 Hz,
1H), 2.85-2.68 (m, 3H), 2.44 (dd, J=5.0, 2.7 Hz, 1H), 1.92-1.74 (m,
2H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 141.12 (s), 128.29
(s), 128.23 (s), 125.87 (s), 51.60 (s), 47.05 (s), 34.15 (s), 32.10
(s).
[0090] Step 3:
##STR00051##
[0091] Under an argon atmosphere at -20.degree. C., (Me).sub.3SI
(30 g, 147 mmol) and 100 mL of anhydrous THF were added to a 250 mL
dry reaction flask, and then 61.2 mL (2.4 M, 147 mmol) of n-butyl
lithium was added dropwise to the reaction solution, and reacted at
-20.degree. C. for 30 minutes. Compound SC-7-1 (4.35, 29.3 mmol)
was dissolved in 10 mL of dry THF, and slowly added dropwise to the
above reaction solution. The reaction solution was then slowly
heated to room temperature, and continuously reacted for 5 hrs. The
reaction was monitored by TLC. After the reaction was completed,
the reaction was terminated by adding a saturated ammonium chloride
aqueous solution. The reaction solution was extracted with ethyl
acetate (100 mL*3), and the organic phases were combined, and dried
with anhydrous sodium sulfate by rotary evaporation. The obtained
crude product was subjected to silica gel column chromatography
with eluent of petroleum ether:ethyl acetate=20:1, to obtain 4.0 g
of a liquid product SC-8-1 as a light yellow oil (yield 85%).
[0092] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.34-7.27 (m, 2H),
7.25-7.18 (m, 3H), 5.92 (ddd, J=17.0, 10.4, 6.2 Hz, 1H), 5.38-5.07
(m, 2H), 4.14 (q, J=6.1 Hz, 1H), 2.85-2.62 (m, 2H), 1.95-1.83 (m,
2H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 141.81 (s), 140.93
(s), 128.41 (s), 128.35 (s), 125.80 (s), 114.91 (s), 72.42 (s),
38.44 (s), 31.57 (s).
Example 7
[0093] The preparation method of another specific intermediate in
Example 4 was as follows:
[0094] Step 1:
##STR00052##
[0095] At room temperature, Compound SC-9 (100 g, 617 mmol) and 700
mL of 2-butanone were added to a 1000 mL dry reaction flask, and
then epichlorohydrin (143 g, 1.5 mol) and anhydrous potassium
carbonate (170 g, 1234 mmol) were added to the reaction solution.
The reaction solution was heated to reflux for 12 hrs. Then, water
was added to stop the reaction. The reaction solution was extracted
with ethyl acetate (200 mL*3), and the organic phases were
combined, and dried with anhydrous sodium sulfate by rotary
evaporation. The obtained crude product was subjected to silica gel
column chromatography with eluent of petroleum ether:ethyl
acetate=20:1, to obtain 112 g of a liquid product as a light SC-10
yellow oil (512 mmol, yield 85%).
[0096] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.36 (t, J=8.0 Hz,
1H), 7.19 (d, J=7.7 Hz, 1H), 7.13 (s, 1H), 7.07 (d, J=8.3 Hz, 1H),
4.26 (dd, J=11.0, 2.7 Hz, 1H), 3.98-3.87 (m, 1H), 3.33 (dt, J=5.8,
2.9 Hz, 1H), 2.86 (dt, J=19.1, 4.4 Hz, 1H), 2.73 (dd, J=4.4, 2.8
Hz, 1H). .sup.13C NMR (151 MHz, CDCl.sub.3) .delta. 170.97 (s),
158.53 (s), 131.76 (q, J=32.2 Hz), 129.96 (s), 123.82 (q, J=272.3
Hz), 118.04 (s), 117.76 (q, J=3.5 Hz), 111.37 (d, J=3.9 Hz), 68.98
(s), 60.22 (s), 49.79 (s), 44.31 (s), 20.81 (s), 14.01 (s).
[0097] Step 2:
##STR00053##
[0098] Under an argon atmosphere at -20.degree. C., (Me).sub.3SI
(30 g, 147 mmol) and 100 mL of anhydrous THF were added to a 250 mL
dry reaction flask, and then 61.2 mL (2.4 M, 147 mmol) of n-butyl
lithium was added dropwise to the reaction solution, and reacted at
-20.degree. C. for 30 minutes. Compound SC-10 (6.38, 29.3 mmol) was
dissolved in 10 mL of dry THF, and slowly added dropwise to the
above reaction solution. The reaction solution was then slowly
heated to room temperature, and continuously reacted for 5 hrs. The
reaction was monitored by TLC. After the reaction was completed,
the reaction was terminated by adding a saturated ammonium chloride
aqueous solution. The reaction solution was extracted with ethyl
acetate (100 mL*3), and the organic phases were combined, and dried
with anhydrous sodium sulfate by rotary evaporation. The obtained
crude product was subjected to silica gel column chromatography
with eluent of petroleum ether:ethyl acetate=20:1, to obtain 6.17 g
of a liquid product SC-11 as a light yellow oil (yield 85%).
[0099] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (t, J=8.0 Hz,
1H), 7.23 (d, J=7.7 Hz, 1H), 7.15 (s, 1H), 7.09 (dd, J=8.3, 2.4 Hz,
1H), 5.96 (ddd, J=17.2, 10.6, 5.7 Hz, 1H), 5.47 (dt, J=17.3, 1.4
Hz, 1H), 5.31 (dt, J=10.6, 1.3 Hz, 1H), 4.65-4.54 (m, 1H), 4.05
(dd, J=9.4, 3.4 Hz, 1H), 3.93 (dd, J=9.4, 7.5 Hz, 1H), 2.44 (d,
J=3.9 Hz, 1H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 158.54
(s), 135.84 (s), 131.81 (q, J=32.4 Hz), 130.00 (s), 123.84 (q,
J=272.3 Hz), 117.99 (s), 117.82 (q, J=3.8 Hz), 117.31 (s), 111.42
(q, J=3.8 Hz), 71.84 (s), 71.03 (s).
Example 8
[0100] The preparation method of another specific intermediate in
Example 4 was as follows:
[0101] Step 1:
##STR00054##
[0102] At room temperature, Compound SC-12 (2 g, 15.6 mmol) and 50
mL of 2-butanone were added to a 1000 mL dry reaction flask, and
then epichlorohydrin (3.6 g, 39 mol) and anhydrous potassium
carbonate (4.3 g, 31.2 mmol) were added to the reaction solution.
The reaction solution was heated to reflux for 12 hrs. Then, water
was added to stop the reaction. The reaction solution was extracted
with ethyl acetate (50 mL*3), and the organic phases were combined,
and dried with anhydrous sodium sulfate by rotary evaporation. The
obtained crude product was subjected to silica gel column
chromatography with eluent of petroleum ether:ethyl acetate=20:1,
to obtain 2.3 g of a liquid product SC-13 as a light yellow oil
(12.6 mmol, yield 81%).
[0103] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.17 (t, J=8.1 Hz,
1H), 6.93 (ddd, J=7.9, 1.9, 0.9 Hz, 1H), 6.90 (t, J=2.2 Hz, 1H),
6.79 (ddd, J=8.4, 2.5, 0.8 Hz, 1H), 4.20 (dd, J=11.0, 2.9 Hz, 1H),
3.85 (dd, J=11.0, 5.9 Hz, 1H), 3.31 (ddt, J=5.7, 4.1, 2.8 Hz, 1H),
2.87 (dd, J=4.8, 4.2 Hz, 1H), 2.71 (dd, J=4.9, 2.7 Hz, 1H).
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 159.00 (s), 134.62 (s),
130.12 (s), 121.15 (s), 114.85 (s), 112.92 (s), 68.79 (s), 49.74
(s), 44.27 (s).
[0104] Step 2:
##STR00055##
[0105] Under an argon atmosphere at -20.degree. C., (Me).sub.3SI
(30 g, 147 mmol) and 100 mL of anhydrous THF were added to a 250 mL
dry reaction flask, and then 61.2 mL (2.4 M, 147 mmol) of n-butyl
lithium was added dropwise to the reaction solution, and reacted at
-20.degree. C. for 30 minutes. Compound SC-13 (5.4 g, 29.3 mmol)
was dissolved in 10 mL of dry THF, and slowly added dropwise to the
above reaction solution. The reaction solution was then slowly
heated to room temperature, and continuously reacted for 5 hrs. The
reaction was monitored by TLC. After the reaction was completed,
the reaction was terminated by adding a saturated ammonium chloride
aqueous solution. The reaction solution was extracted with ethyl
acetate (100 mL*3), and the organic phases were combined, and dried
with anhydrous sodium sulfate by rotary evaporation. The obtained
crude product was subjected to silica gel column chromatography
with eluent of petroleum ether:ethyl acetate=20:1, to obtain 4.95 g
of a liquid product SC-14 as a light yellow oil (yield 85%).
[0106] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.19 (t, J=8.1 Hz,
1H), 6.95 (ddd, J=7.9, 1.9, 0.8 Hz, 1H), 6.91 (t, J=2.2 Hz, 1H),
6.80 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 5.93 (ddd, J=17.2, 10.6, 5.6
Hz, 1H), 5.45 (dt, J=17.3, 1.4 Hz, 1H), 5.29 (dt, J=10.6, 1.3 Hz,
1H), 4.66-4.49 (m, 1H), 3.99 (dd, J=9.4, 3.5 Hz, 1H), 3.87 (dd,
J=9.4, 7.6 Hz, 1H), 2.58 (d, J=3.7 Hz, 1H). .sup.13C NMR (101 MHz,
CDCl.sub.3) .delta. 159.10 (s), 135.80 (s), 134.83 (s), 130.23 (s),
121.36 (s), 117.31 (s), 115.01 (s), 113.03 (s), 71.80 (s), 71.00
(s).
Example 9
[0107] Preparation of Prostaglandin Compound PGF.sub.2.alpha.
##STR00056##
[0108] Step 1:
##STR00057##
[0109] In an argon-filled glove box, Compound S8 (22 mg, 0.1 mmol),
SC-4 (65.5 mg, 0.5 mmol) and second-generation Hovedy-Grubbs
catalyst (6.2 mg, 0.01 mmol) were dissolved in anhydrous and
anaerobic DCM (2 mL). Then the reaction system was heated to
60.degree. C. and stirred for 5 hrs. The reaction was monitored by
TLC. After the reaction was completed, the reaction solution was
dried by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=1:1, to obtain 27 mg of a liquid
product S11 as a light yellow oil (yield 95%), and 6 mg of raw
material was recovered.
[0110] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 5.55 (dd, J=15.2,
7.3 Hz, 1H), 5.41 (dd, J=15.2, 9.1 Hz, 1H), 4.89 (t, J=4.0 Hz, 1H),
4.20 (s, 1H), 4.07-3.98 (m, 2H), 3.96 (dd, J=10.8, 6.3 Hz, 1H),
3.86 (ddt, J=18.7, 12.2, 6.2 Hz, 3H), 3.13 (s, 2H), 2.44 (s, 1H),
2.37-2.28 (m, 1H), 2.25 (dd, J=17.1, 9.8 Hz, 1H), 1.92 (s, 1H),
1.87-1.81 (m, 2H), 1.73-1.64 (m, 2H), 1.59-1.51 (m, 1H), 1.50-1.41
(m, 1H), 1.39-1.23 (m, 6H), 0.87 (t, J=6.7 Hz, 3H). .sup.13C NMR
(151 MHz, CDCl.sub.3) .delta. 136.01 (s), 132.15 (s), 103.81 (s),
77.15 (s), 72.96 (s), 71.96 (s), 65.16 (s), 64.61 (s), 55.82 (s),
44.87 (s), 41.80 (s), 37.20 (s), 31.70 (s), 31.07 (s), 25.19 (s),
22.57 (s), 13.99 (s).
[0111] Step 2:
##STR00058##
[0112] Compound S1l (35 mg, 0.11 mmol), 5 mL of THF and 1 mL of
deionized water were added to a 25 mL reaction flask, and then TsOH
(1.7 mg, 0.01 mmol) was added to the reaction solution in one
portion, and reacted at 75.degree. C. for 3 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated sodium bicarbonate aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product S12 was directly used in the next reaction. Under an argon
atmosphere at -78.degree. C., Compound S13 (243 mg, 0.55 mmol) and
5 mL of anhydrous THF were added to a 25 mL dry reaction flask, and
then 1.1 mL (1 M, 1.1 mmol) of i-butyl lithium was added dropwise
to the reaction solution, and reacted at -78.degree. C. for 30
minutes. Then the freshly prepared compound S12 above was dissolved
in 2 mL of dry THF, and slowly added dropwise to the above reaction
solution. The reaction solution was then heated to room
temperature, and continuously reacted for 2 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated ammonium chloride aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product was subjected to silica gel column chromatography with
eluent of petroleum ether:ethyl acetate=1:1, to obtain 21 mg of a
liquid product PG.sub.2.alpha. as a light yellow oil (yield of two
steps: 55%).
[0113] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 5.56 (dd, J=15.3,
7.0 Hz, 1H), 5.46 (ddd, J=19.9, 14.7, 8.0 Hz, 2H), 5.40-5.30 (m,
1H), 4.29 (s, 3H), 4.16 (s, 1H), 4.08 (dt, J=16.4, 8.2 Hz, 1H),
3.94 (s, 1H), 2.33 (t, J=6.4 Hz, 3H), 2.28-2.17 (m, 2H), 2.11 (dd,
J=13.1, 6.9 Hz, 3H), 1.74 (d, J=14.6 Hz, 1H), 1.67 (dd, J=16.9,
13.0 Hz, 2H), 1.61-1.53 (m, 1H), 1.46 (dt, J=26.4, 8.9 Hz, 2H),
1.39-1.22 (m, 8H), 0.88 (t, J=6.7 Hz, 3H). .sup.13C NMR (151 MHz,
CDCl.sub.3) .delta. 134.91 (s), 132.63 (s), 129.61 (s), 129.16 (s),
77.68 (s), 73.12 (s), 72.57 (s), 55.38 (s), 50.30 (s), 42.72 (s),
36.94 (s), 32.99 (s), 31.71 (s), 26.27 (s), 25.22 (s), 24.51 (s),
22.61 (s), 14.02 (s).
Example 10
[0114] Preparation of Prostaglandin Compound Travoprost:
##STR00059##
[0115] Step 1:
##STR00060##
[0116] In an argon-filled glove box, Compound S8 (43 mg, 0.2 mmol),
SC-11 (243 mg, 1.0 mmol) and second-generation Hovedy-Grubbs
catalyst (12 mg, 0.02 mmol) were dissolved in anhydrous and
anaerobic DCM (2 mL). Then the reaction system was heated to
60.degree. C. and stirred for 5 hrs. The reaction was monitored by
TLC. After the reaction was completed, the reaction solution was
dried by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=1:1, to obtain 68 mg of a liquid
product S14 as a light yellow oil (yield 82%).
[0117] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.36 (t, J=8.0 Hz,
1H), 7.19 (d, J=7.7 Hz, 1H), 7.13 (s, 1H), 7.06 (dd, J=8.3, 2.0 Hz,
1H), 5.73-5.62 (m, 2H), 4.87 (dd, J=4.7, 3.1 Hz, 1H), 4.51 (d,
1=3.4 Hz, 1H), 4.20 (s, 1H), 4.06-3.75 (m, 7H), 3.37-3.18 (m, 3H),
2.29 (dt, J=8.0, 6.8 Hz, 2H), 1.95-1.78 (m, 2H), 1.77-1.65 (in,
2H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 158.59 (s), 133.88
(s), 131.76 (q, J=32.3 Hz), 130.08 (s), 129.98 (s), 123.84 (q,
J=272.3 Hz), 117.94 (s), 117.70 (q, J=3.6 Hz), 111.51 (q, J=3.8
Hz), 103.66 (s), 77.09 (s), 72.01 (d, J=3.6 Hz), 70.19 (s), 65.10
(s), 64.54 (s), 55.79 (s), 44.82 (s), 41.83 (s), 30.98 (s).
[0118] Step 2:
##STR00061##
[0119] Compound S14 (46 mg, 0.11 mmol), 5 mL of THF and 1 mL of
deionized water were added to a 25 mL reaction flask, and then TsOH
(1.9 mg, 0.015 mmol) was added to the reaction solution in one
portion, and reacted at 75.degree. C. for 3 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated sodium bicarbonate aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained S15
crude product was directly used in the next reaction. Under an
argon atmosphere at -78.degree. C., Compound S13 (243 mg, 0.55
mmol) and 5 mL of anhydrous THF were added to a 25 mL dry reaction
flask, and then 1.1 mL (1 M, 1.1 mmol) of n-butyl lithium was added
dropwise to the reaction solution, and reacted at -78.degree. C.
for 30 minutes. Then the freshly prepared compound S15 above was
dissolved in 2 mL of dry THF, and slowly added dropwise to the
above reaction solution. The reaction was then heated to room
temperature, and continuously reacted for 2 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated ammonium chloride aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product was subjected to silica gel column chromatography with
eluent of petroleum ether:ethyl acetate=1:1, to obtain 40 mg of a
liquid product Fluprostenol as a light yellow oil (yield of two
steps: 80%).
[0120] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.40 (t, J=8.0 Hz,
1H), 7.23 (d, J=7.7 Hz, 1H), 7.15 (s, 1H), 7.09 (dd, J=8.3, 2.3 Hz,
1H), 5.71 (ddd, J=21.7, 15.3, 7.6 Hz, 2H), 5.52 (dd, J=17.7, 7.7
Hz, 1H), 5.40 (dd, J=18.3, 7.8 Hz, 1H), 4.60 (td, J=7.2, 3.3 Hz,
1H), 4.24 (s, 1H), 4.09-3.95 (m, 3H), 2.77 (s, 4H), 2.43-2.23 (m,
5H), 2.20-2.04 (m, 5H), 1.82 (d, J=14.7 Hz, 1H), 1.66 (ddt, J=26.6,
13.7, 7.0 Hz, 2H), 1.55-1.48 (m, 1H). .sup.13C NMR (151 MHz,
CDCl.sub.3) .delta. 158.49 (s), 135.95 (s), 131.95 (q, J=32.2 Hz),
130.10 (s), 129.84 (s), 128.81 (s), 128.78 (s), 126.66-120.94 (m),
118.08 (s), 117.99 (q, J=3.5 Hz), 111.51 (d, J=3.6 Hz), 78.00 (s),
72.86 (s), 71.82 (s), 71.18 (s), 56.33 (s), 51.17 (s), 43.17 (s),
32.56 (s), 29.69 (s), 26.12 (s), 25.07 (s), 24.49 (s).
Example 11
[0121] Method for preparing Travoprost with Compound
Fluprostenol:
##STR00062##
[0122] Fluprostenol (20 mg, 0.043 mmol) and 2 mL of DMF were added
to a 25 mL reaction flask, and then CsCO.sub.3 (21.1 mg, 0.065
mmol) was added to the reaction solution in one portion, and
reacted at room temperature for 24 hrs. The reaction was monitored
by TLC. After the reaction was completed, water was added to stop
the reaction. The reaction solution was extracted with ethyl
acetate (5 mL*3), and the organic phases were combined, and dried
with anhydrous sodium sulfate by rotary evaporation. The obtained
crude product was subjected to silica gel column chromatography
with eluent of petroleum ether:ethyl acetate=8:1, to obtain 18 mg
of a liquid product Travoprost as a light yellow oil (yield
86%).
[0123] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.39 (t, J=8.0 Hz,
1H), 7.22 (d, J=7.7 Hz, 1H), 7.15 (s, 1H), 7.09 (dd, J=8.3, 2.2 Hz,
1H), 5.83-5.62 (m, 2H), 5.52-5.34 (m, 2H), 4.99 (hept, J=6.3 Hz,
1H), 4.54 (dd, J=10.8, 5.3 Hz, 1H), 4.21 (d, J=2.9 Hz, 1H),
4.07-3.89 (m, 3H), 2.71 (d, J=3.7 Hz, 1H), 2.48 (d, J=6.5 Hz, 1H),
2.40 (ddd, J=10.4, 8.6, 4.7 Hz, 1H), 2.35-2.24 (m, 4H), 2.21-2.04
(m, 4H), 1.82 (dd, J=14.5, 2.0 Hz, 1H), 1.73-1.62 (m, 3H), 1.57
(ddd, J=14.8, 10.3, 4.4 Hz, 1H), 1.22 (dt, J=6.3, 3.0 Hz, 6H).
.sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 173.59 (s), 158.62 (s),
134.86 (s), 131.89 (q, J=32.3 Hz), 130.04 (s), 129.89 (s), 129.34
(s), 128.93 (s), 123.86 (q, J=272.4 Hz), 118.05 (s), 117.84 (dd,
J=7.7, 3.8 Hz), 111.45 (q, J=3.8 Hz), 78.25 (s), 73.11 (s), 72.10
(s), 70.67 (s), 67.76 (s), 56.16 (s), 50.76 (s), 42.98 (s), 33.92
(s), 26.57 (s), 25.57 (s), 24.81 (s), 21.81 (s).
Example 12
[0124] Preparation of Prostaglandin Compound Cloprostenol:
[0125] The reaction route was shown below:
##STR00063##
[0126] Step 1:
##STR00064##
[0127] In an argon-filled glove box, Compound S8 (22 mg, 0.1 mmol),
SC-14 (97 mg, 0.5 mmol) and second-generation Hovedy-Grubbs
catalyst (6 mg, 0.01 mmol) were dissolved in anhydrous and
anaerobic DCM (2 mL). Then the reaction system was heated to
60.degree. C. and stirred for 5 hrs. The reaction was monitored by
TLC. After the reaction was completed, the reaction solution was
dried by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=1:1, to obtain 35 mg of a liquid
product S16 as a light yellow oil (yield 86%).
[0128] 1H NMR (600 MHz, CDCl.sub.3) .delta. 7.17 (q, J=7.8 Hz, 1H),
6.96-6.85 (m, 2H), 6.79 (dd, J=8.3, 2.3 Hz, 1H), 5.73-5.58 (m, 2H),
4.88 (dd, J=5.0, 2.9 Hz, 1H), 4.57-4.44 (m, 1H), 4.21 (s, 1H),
4.04-3.98 (m, 1H), 3.98-3.92 (m, 2H), 3.90-3.81 (m, 4H), 3.24 (d,
J=35.0 Hz, 1H), 3.10 (s, 2H), 2.30 (qd, J=14.1, 8.5 Hz, 2H),
1.97-1.80 (m, 2H), 1.78-1.67 (m, 2H). .sup.13C NMR (151 MHz,
CDCl.sub.3) .delta. 159.19 (s), 134.81 (s), 133.88 (s), 130.22 (s),
130.06 (s), 121.26 (s), 115.10 (s), 113.03 (s), 103.69 (s), 77.14
(s), 72.09 (s), 71.99 (s), 70.23 (s), 65.12 (s), 64.57 (s), 55.86
(s), 44.89 (s), 41.84 (s), 31.03 (s).
[0129] Step 2:
##STR00065##
[0130] Compound S16 (45 mg, 0.11 mmol), 5 mL of THF and 1 mL of
deionized water were added to a 25 mL reaction flask, and then TsOH
(2.58 mg, 0.015 mmol) was added to the reaction solution in one
portion, and reacted at 75.degree. C. for 3 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated sodium bicarbonate aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product S17 was directly used in the next reaction. Under an argon
atmosphere at -78.degree. C., Compound S13 (243 mg, 0.55 mmol) and
5 mL of anhydrous THF were added to a 25 mL dry reaction flask, and
then 1.1 mL (1 M, 1.1 mmol) of n-butyl lithium was added dropwise
to the reaction solution, and reacted at -78.degree. C. for 30
minutes. Then the freshly prepared compound S17 above was dissolved
in 2 mL of dry THF, and slowly added dropwise to the above reaction
solution. The reaction solution was then heated to room
temperature, and continuously reacted for 2 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated ammonium chloride aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product was subjected to silica gel column chromatography with
eluent of petroleum ether:ethyl acetate=1:1, to obtain 34 mg of a
liquid product Cloprostenol as a light yellow oil (yield of two
steps: 69%).
[0131] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.20 (t, J=8.1 Hz,
1H), 6.97-6.94 (m, 1H), 6.92 (s, 1H), 6.81 (dd, J=8.3, 2.3 Hz, 1H),
5.69 (ddd, J=21.6, 15.2, 7.5 Hz, 2H), 5.52 (dd, J=17.7, 7.4 Hz,
1H), 5.39 (dd, J=18.0, 7.9 Hz, 1H), 4.62-4.53 (m, 1H), 4.23 (s,
1H), 4.10-3.96 (m, 2H), 3.93 (dd, J=22.7, 14.6 Hz, 1H), 2.82 (d,
J=6.4 Hz, 4H), 2.36 (dd, J=18.9, 14.2 Hz, 3H), 2.30-2.23 (m, 1H),
2.21-2.05 (m, 4H), 1.81 (d, J=14.4 Hz, 1H), 1.66 (tt, J=20.8, 6.8
Hz, 2H), 1.50 (dd, J=12.7, 8.8 Hz, 1H). .sup.13C NMR (151 MHz,
CDCl.sub.3) .delta. 177.21 (s), 159.18 (s), 134.92 (s), 134.83 (s),
130.28 (s), 129.65 (s), 129.52 (s), 128.97 (s), 121.32 (s), 115.12
(s), 113.10 (s), 77.56 (s), 72.50 (s), 71.78 (s), 70.72 (s), 55.49
(s), 50.52 (s), 42.86 (s), 32.82 (s), 26.20 (s), 25.04 (s).
Example 13
[0132] Preparation of prostaglandin compound Latanoprost
##STR00066##
[0133] Step 1:
##STR00067##
[0134] In an argon-filled glove box, Compound S8 (48 mg, 0.2 mmol),
SC-8-1 (162 mg, 0.5 mmol) and second-generation Hovedy-Grubbs
catalyst (12.5 mg, 0.02 mmol) were dissolved in anhydrous and
anaerobic DCM (2 mL). Then the reaction system was heated to
60.degree. C. and stirred for 5 hrs. The reaction was monitored by
TLC. After the reaction was completed, the reaction solution was
dried by rotary evaporation. The obtained crude product was
subjected to silica gel column chromatography with eluent of
petroleum ether:ethyl acetate=1:1, to obtain 54 mg of a liquid
product S18 as a light yellow oil (yield 78%).
[0135] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.27 (dd, J=9.0,
5.9 Hz, 2H), 7.21-7.14 (m, 2H), 5.73-5.54 (m, 1H), 5.50-5.31 (m,
1H), 4.89 (t, J=3.8 Hz, 1H), 4.20 (s, 1H), 4.12-3.92 (m, 3H),
3.92-3.74 (m, 3H), 3.34 (d, J=58.2 Hz, 1H), 3.20 (s, 1H), 2.85 (s,
1H), 2.78-2.60 (m, 2H), 2.39-2.30 (m, 1H), 2.26 (dd, J=17.4, 9.9
Hz, 1H), 2.05 (s, 1H), 1.96-1.75 (m, 4H), 1.69 (ddt, J=15.2, 9.9,
4.9 Hz, 2H). .sup.13C NMR (101 MHz, CDCl.sub.3) .delta. 141.91 (s),
135.97 (s), 132.74 (s), 128.42 (s), 128.29 (s), 125.71 (s), 103.68
(s), 76.76 (s), 72.24 (s), 71.56 (s), 65.10 (s), 64.57 (s), 55.43
(s), 44.36 (s), 41.74 (s), 38.66 (s), 31.80 (s), 30.84 (s).
[0136] Step 2:
##STR00068##
[0137] Compound S18 (28 mg, 0.08 mmol), 10 mg of palladium on
carbon, 2 mL of ethanol and 40 .mu.l of sodium hydroxide aqueous
solution (1.0 M, 40 .mu.mol) were added to a 25 mL reaction flask,
the reactor was purged three times with hydrogen and then
introduced with 1 atm of hydrogen. The reaction was continued at
room temperature for 5 hrs. The reaction was monitored by TLC.
After the reaction was completed, the palladium on carbon was
filtered off, and the solvent was removed by rotary evaporation.
The obtained crude product S19 was directly used in the next
reaction.
[0138] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.20 (t, J=7.4 Hz,
2H), 7.15-7.08 (m, 3H), 4.84 (dd, J=13.3, 9.5 Hz, 1H), 4.15 (s,
1H), 3.99-3.86 (m, 2H), 3.86-3.74 (m, 3H), 3.65-3.51 (m, 1H), 3.13
(s, 2H), 2.81-2.66 (m, 1H), 2.65-2.52 (m, 1H), 1.94-1.78 (m, 4H),
1.71 (ddd, J=23.1, 11.7, 6.9 Hz, 2H), 1.66-1.58 (m, 1H), 1.56-1.45
(m, 3H), 1.38 (tt, J=19.2, 9.6 Hz, 1H), 1.29 (ddd, J=22.1, 14.6,
7.4 Hz, 1H). .sup.13C NMR (151 MHz, CDCl.sub.3) .delta. 142.08 (s),
128.37 (s), 128.36 (s), 125.75 (s), 103.81 (s), 78.17 (s), 74.35
(s), 71.20 (s), 65.10 (s), 64.58 (s), 53.32 (s), 46.83 (s), 41.66
(s), 39.04 (s), 35.57 (s), 32.86 (s), 32.07 (s), 29.35 (s).
Example 14
[0139] Preparation of prostaglandin compound Latanoprost
[0140] Step 1:
##STR00069##
[0141] Compound S19 (54 mg, 0.15 mmol), 5 mL of THF and 1 mL of
deionized water were added to a 25 mL reaction flask, and then TsOH
(2.5 mg, 0.015 mmol) was added to the reaction solution in one
portion, and reacted at 75.degree. C. for 3 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated sodium bicarbonate aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product S20 was directly used in the next reaction. Under an argon
atmosphere at -78.degree. C., Compound S13 (332 mg, 0.75 mmol) and
5 mL of anhydrous THF were added to a 25 mL dry reaction flask, and
then 1.5 mL (1 M, 1.5 mmol) of n-butyl lithium was added dropwise
to the reaction solution, and reacted at -78.degree. C. for 30
minutes. Then the freshly prepared compound S20 above was dissolved
in 2 mL of dry THF, and slowly added dropwise to the above reaction
solution. The reaction solution was then heated to room
temperature, and continuously reacted for 2 hrs. The reaction was
monitored by TLC. After the reaction was completed, the reaction
was terminated by adding a saturated ammonium chloride aqueous
solution. The reaction solution was extracted with ethyl acetate (5
mL*3), and the organic phases were combined, and dried with
anhydrous sodium sulfate by rotary evaporation. The obtained crude
product was subjected to silica gel column chromatography with
eluent of petroleum ether:ethyl acetate=1:1, to obtain 32 mg of a
liquid product Latanoprost acid as a light yellow oil (yield of two
steps: 55%).
[0142] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.35-7.24 (m, 2H),
7.26-7.12 (m, 3H), 5.59-5.45 (m, 1H), 5.45-5.26 (m, 1H), 4.14 (d,
J=23.8 Hz, 2H), 3.98-3.90 (m, 2H), 3.74-3.62 (m, 1H), 2.86-2.74 (m,
1H), 2.65 (ddd, J=19.4, 15.6, 9.5 Hz, 1H), 2.34 (dd, J=14.5, 7.8
Hz, 2H), 2.30-2.21 (m, 2H), 2.15 (td, J=14.9, 7.6 Hz, 2H),
1.93-1.82 (m, 2H), 1.81-1.74 (m, 2H), 1.73-1.65 (m, 3H), 1.61 (dd,
J=13.8, 7.2 Hz, 2H), 1.53 (ddd, J=16.2, 12.0, 7.1 Hz, 1H),
1.40-1.30 (m, 2H). .sup.13C NMR (151 MHz, CDCl.sub.3) .delta.
177.26 (s), 142.05 (s), 129.45 (d, J=8.5 Hz), 128.40 (s), 125.82
(s), 78.55 (s), 74.43 (s), 71.52 (s), 52.39 (s), 51.66 (s), 42.48
(s), 38.73 (s), 35.19 (s), 33.04 (s), 32.08 (s), 29.04 (s), 26.63
(s), 26.35 (s), 24.63 (s).
[0143] Step 2:
##STR00070##
[0144] Latanoprost acid (30 mg, 0.076 mmol) and 2 mL of DMF were
added to a 25 mL reaction flask, and then CsCO.sub.3 (37 mg, 0.114
mmol) was added to the reaction solution in one portion. The
reaction was continued at room temperature for 24 hrs. The reaction
was monitored by TLC. After the reaction was completed, water was
added to stop the reaction. The reaction solution was extracted
with ethyl acetate (5 mL*3), and the organic phases were combined,
and dried with anhydrous sodium sulfate by rotary evaporation. The
obtained crude product was subjected to silica gel column
chromatography with eluent of petroleum ether:ethyl acetate=1:1, to
obtain 24 mg of a liquid product Latanoprost as a light yellow oil
(yield 73%).
[0145] .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 7.24-7.18 (m, 2H),
7.17-7.08 (m, 3H), 5.39 (dt, J=10.8, 7.2 Hz, 1H), 5.31 (dt, J=18.0,
7.1 Hz, 1H), 5.02-4.88 (m, 1H), 4.09 (s, 1H), 3.89 (d, J=23.0 Hz,
1H), 3.66-3.54 (m, 1H), 2.77-2.68 (m, 1H), 2.66-2.57 (m, 1H), 2.44
(s, 1H), 2.29-2.19 (m, 3H), 2.14 (ddd, J=15.9, 11.5, 5.7 Hz, 1H),
2.06 (tq, J=14.5, 7.2 Hz, 2H), 1.85-1.75 (m, 3H), 1.75-1.68 (m,
2H), 1.65-1.58 (m, 3H), 1.57-1.51 (m, 2H), 1.50-1.42 (m, 1H),
1.36-1.24 (m, 2H), 1.19-1.11 (m, 6H). .sup.13C NMR (151 MHz,
CDCl.sub.3) .delta. 173.46 (s), 142.09 (s), 129.56 (s), 129.34 (s),
128.38 (s), 125.79 (s), 78.75 (s), 74.65 (s), 71.29 (s), 67.64 (s),
52.85 (s), 51.86 (s), 42.51 (s), 39.04 (s), 35.78 (s), 34.05 (s),
32.10 (s), 29.61 (s), 26.88 (s), 26.62 (s), 24.92 (s), 21.81
(s).
[0146] Referring to the aforementioned synthetic route, the
intermediates can be used in the preparation of compounds shown in
FIG. 1.
[0147] Preferred embodiments of the present invention have been
described above. However, the present invention is not limited
thereto. Any other changes, modifications, alternatives,
combinations, simplifications made without departing from the
spirit and principle of the present invention are all equivalent
replacements, and fall in the protection scope of the present
invention.
* * * * *